Department of Pharmaceutics, Acharya Nagarjuna University College of Pharmaceutical Sciences Guntur-522510.
One of the most promising new forms of nanotechnology, SLN have numerous possible uses in areas as diverse as medication delivery, clinical treatment, research, and other domains of biology. Lipophilic or hydrophilic medications dissolve round SLN particles in water or aqueous surfactant solutions, which are in the nanometer range. To further circumvent the harmful effects of conventional drug carrier systems, it is necessary to employ alternative biodegradable and biocompatible polymers to increase the bioavailability and solubility of weakly soluble pharmaceuticals. Several conventional carrier systems were compared and evaluated, as well as the numerous development methodologies, in this review paper. Comprehensive manufacturing processes, such as solvent evaporation and homogenization, are also highlighted in this study as means to lessen the harmful and overdose consequences of pharmaceuticals. By utilizing latest technology analytical techniques such as advanced imaging techniques, nuclear magnetic resonance imaging, DSC, atomic force microscopy, DLS, and electron microscopy, SLNs have the ability to be used as individualized medication delivery systems.
In recent decades, the area of nanotechnology have revolutionized pharmaceutical sciences, offering innovative strategies for drug delivery, diagnosis, and therapy. Among various nanoparticulate systems, SLNs have garnered significant attention to provide drugs in an innovative and efficient manner. First introduced in the early 1990s, Solid lipid nano particles come together the advantages of usual colloidal carriers—such as nanoparticles made of polymers, emulsions, and liposomes while addressing many of their limitations, including instability, potential toxicity, and scale-up challenges. SLNs are submicron-sized carriers (typically ranging from 50 to 1000 nm and composed of physiological lipids that maintain a solid state at both room and body temperatures. These lipids, often derived from natural or biocompatible sources, are hydrolyzed and stabilized using surfactants. The solid matrix of SLNs offers a protective environment for encapsulated therapeutic agents, ensuring their stability against chemical and enzymatic degradation. Furthermore, the use of biodegradable and biocompatible lipids minimizes toxicity, making SLNs appropriate for various uses in the biological field.[1] The ability of SLNs to include sensitive Biological molecules such as proteins, peptides, genetic material, and hydrophilic and lipophilic medicines is one of their most remarkable features. Drug pharmacokinetics and bioavailability, dosage frequency, and systemic adverse effect mitigation can all be enhanced with the regulated and targeted release profiles provided by SLNs.[2] When it comes to treating complex and long-lasting diseases like cancer, neurological disorders, and infectious diseases, these traits really shine. Cosmetics and nutraceuticals are two further areas where SLNs have shown considerable promise, alongside pharmaceuticals. Skin penetration, photo stability, and extended release are three of their best properties, making them perfect for topical applications.[3,4] Although SLNs have numerous benefits, they do have some limits. Constant investigation into ways to enhance their design and functionality has been motivated by concerns including low drug loading capacity, possible lipid matrix polymorphism transitions, and stability issues during storage. To address some of these limitations, new variants such as nano structured lipid carriers (NLCs) have been created. Formulation methods, physicochemical properties, drug loading mechanisms, administration routes, and present and future therapeutic uses of solid lipid nano particles are all part of the purpose of this review paper. We focus on the current state of SLNs, the difficulties we still face, and our hopes for their future as a scalable and dependable drug delivery method in contemporary medicine.
2. Composition of SLNs:
A SLNs physicochemical characteristics, stability, drug loading capacity, and biological function are all heavily influenced by its ingredient makeup.[5] Lipids, surfactants (emulsifiers), and solvents or co-surfactants are the three main ingredients of SLNs. The physicochemical properties of the medicine and its intended delivery method dictate the meticulous selection of each component.
2.1 Lipids:
The lipid matrix encapsulates the medicine and regulates its release; it is the primary component of SLNs. Lipids must remain in a solid form at both ambient and metabolic temperatures. How the medication is released from the SLN is impacted by its crystalline form, loading efficiency, and the solubility of the drug, all of which are affected by the lipid choice. Triglycerides and partial glycerides are lipids that are commonly employed. They Fatty acids, such as palmitic and stearic acids Cetyl palmitate and carnauba wax are two examples of waxes; cholesterol is an example of a sterol.
2.2 Surfactants (Emulsifiers):
Dispersed lipid particles in a water-based dispersion medium are stabilized with the help of surfactants, which lower surface tension and inhibit aggregation. In addition to impacting the formulation's stability, they affect particle dimensions and zeta potential. To guarantee a stable nanoparticle dispersion free of harmful effects, an ideal surfactant concentration is required.[6] Here are some common surfactants: Tween 80, Tween 20, Poloxamer 188, Poloxamer 407 are non-ionic surfactants. Natural emulsifiers: lecithin (phospholipids from soybeans or eggs) Ionic surfactants: sodium dodecyl sulfate (SDS)
2.3 Co-surfactants and Co-solvents
When it comes to improving emulsification, reducing interfacial tension, and enhancing medication solubility in the lipid phase, co-surfactants or co-solvents are occasionally introduced. In particular, these ingredients aid in emulsification by reducing particle size and increasing formulation stability. Here are a few examples: Propylene glycol , Ethanol , Butanol PEG 400.
3.Preparation of Solid Lipid Nanoparticles:
Controlled drug release, increased drug stability, and high bioavailability are all benefits of SLNs, a form of colloidal medication administration technique. Stabilization is achieved by surfactants along with comprise solid lipids at both ambient and core temperatures. [7]
High shears homogenization:
Lipid that exists in solid form High shear homogenization was the first method used to create nanoparticle dispersions. You can easily handle both strategies, and they are widely used. The process of melt emulsification is utilized in this way to create SLN. Many process variables, including stirring speed, emulsification duration, and cooling environment, were investigated by Olbrich for their impact on particle size. The lipids used in this formulation include trimyristin, tripalmitin, and a mix of mono-, di-, and triglycerides . Steric stabilizers include substances like glycerol behenate and poloxymer 188. When it comes to SLN performance, stir the Witepsol W35 dispersions at room temperature for 8 minutes at 20,000 rpm. Let them cool for 10 minutes, and then stir them again at 5000 rpm. Alternatively, Dynasan116 dispersions performed best when emulsified for 10 minutes at 25,000 rpm and then cooled for 5 minutes at 5,000 rpm in cold water. Although the particle size remains unchanged, the poly dispersity index shows a small improvement with higher stirring rates. [8,9]
Hot homogenization:
The procedure is carried out at temperatures greater than the melting point of the lipid. An emulsion homogenization provides a useful comparison. An apparatus for vigorous mixing, similar to a homogenizer of the Silverson type, is employed to simultaneously produce the drug-loaded lipid melt pre-emulsion and the aqueous emulsifier phase. But pre-emulsion is an issue since it drastically reduces the final product quality. Homogenization of the pre-emulsion occurs at high pressure, which is greater than the lipids' melting point. Due to the decreased viscosity of the lipid phase, smaller particles are usually obtained at higher processing temperatures. The drug and its carrier may also undergo accelerated degradation due to this. An average of three or five runs through the high-pressure homogenizer are required to obtain high-quality goods. There is no way around the fact that the temperature of the sample will increase by about 10°Cat 500bar during high pressure processing. Three to five homogenization cycles at 500 to 1500 bar should be sufficient in most cases. The increased kinetic energy of the particles causes them to coalesce, leading to a larger particle size as homogenization levels rise. [10,11]
Cold homogenization:
Cold homogenization is like milling a suspension under pressure since it uses solid lipids. Maintaining the lipid's solid state during homogenization can be achieved with the help of effective temperature regulation. Its creation is a response to issues using the thermal homogenization technique, including: Substance loss in the aqueous phase upon homogenization. The nano emulsion's complicated crystallization procedure causes the lipid to undergo polymorphic transitions, which in turn cause many changes. Dispersing the medicine in the lipid melt is the first early stages preparation, which is identical to the heat homogenization process. Nevertheless, the procedures that follow are different from the heat homogenization process. The medicine that is melting is chilled quickly (with dry ice) so that it can be distributed consistently across the lipid membrane. The solid lipid medication is ground to a tiny powder. A solution of emulsifiers is cooled and then mixed with the SLNs. Under controlled conditions, the dispersion is heated to room temperature or below and then homogenized under high pressure. Cold homogenization typically produces particles with larger diameters and a more even distribution of sizes when contrasted with heat homogenization. [12]
Ultra sonication: [13,14]
A process called sonication, which involves swirling at high speeds, was also employed in the production of solid lipid nanoparticles. The wider particle size distribution, which can reach the micro meter range, is an issue with this approach. This leads to physical instability, such as the formation of particles in the mixture when it is stored. Another big issue with ultra sonication is the possibility of metal contamination. Consequently, several research groups have shown that a combination of high-speed stirring and ultra sonication carried out at high temperatures produces a stable formulation.
Methods for preparing SLNs using micro emulsions:
Gasco and colleagues developed micro emulsion dilution-based SLN preparation methods. Included in this mixture are stearic acid, water, and two emulsifiers, polysorbate 20 and polysorbate 60 are stirred together in an optically transparent mixture to make them.[15] Dissolve the micro emulsion in cold water while stirring. What happens throughout the dilution process depends on the micro emulsion's composition. Due to the presence of the droplet structure Particles smaller than 1 micrometer can be achieved in the micro emulsion state without the need of energy. A volume ratio of 1:25-2:50 is typical for hot micro emulsions in cold water. Polymer particles were created by the scientist Fessi by diluting polymer solutions in water. De La Tourette postulates that the distribution processes' velocities dictate the sizes of the particles. The use of solvents that disperse quickly into water (acetone) allowed in order to create nanoparticles, while the utilize of more lipophilic solvents resulted in bigger particle sizes. It is possible that the micro emulsion's hydrophilic co-solvents, like acetone does for polymer nanoparticle creation, have a comparable function in when lipid nanoparticles are formed [17,18,19]
SLN preparation by using supercritical fluid:
A novel approach that offers the benefit of solvent-less processing is SLN preparation by means of supercritical fluid. Many different kinds of powders and nanoparticles can be made using this platform technology. When making SLN, the RESS technique is used. Purified carbon dioxide is used as a solvent in this process. [20,21,22]
SLN prepared by solvent emulsification/ evaporation:
By dissolving the lipophilic material in an organic solvent (cyclohexane), which is insoluble in water, and then emulsifying it in a water-based phase, one can create nanoparticle dispersions through precipitation in oil-in-water emulsions. A dispersion of nanoparticles is produced when a solvent evaporates and the lipid in the solution precipitates out. The particles that were gathered had an average size of 25 nm. In this case, the model drug is cholesterol acetate, and an emulsifier consisting of a combination of sodium glycocholate and lecithin is used. Siekmann and Westesen produced acetate nanoparticles with an average size of 29 nm. [23,24]
Spray drying method:
Spray drying is a method used to turn an aqueous SLN dispersion into a pharmaceutical product as an alternative to lyophilization. In comparison, it is less expensive than lyophilization. High temperatures, shear pressures, and partial melting cause particles to clump together during this process. Lipids with melting points above 700 are recommended by Freitas and Mullera for spray drying. The best results were obtained with a 1% SLN solution in water or a 20% trehalose in ethanol-water mixture (10/90 v/v). [25]
Double emulsion method:
To create hydrophilic loaded SLN, a novel method based on solvent emulsification-evaporation has been used. The medication is kept from partitioning to the exterior water phase of the w/o/w double emulsion during solvent evaporation by encapsulating it with a stabilizer in that phase. [26]
Characterization of SLNs:
SLNs characterisation is an important aspect of creating efficient drug delivery systems. The lipid-based carriers known as SLNs are submicron sized and provide regulated drug release, protection for pharmaceuticals that are easily dissolved in water, and improved bioavailability. Their pharmacological, physiological, and therapeutic stability, as well as their effectiveness, are guaranteed by thorough characterization. [27]
1. Particle Size and Polydispersity Index (PDI)
All three of these aspects of SLNs—drug release rate, biodistribution, and cellular uptake—are affected by particle size. One measure of particle dispersion homogeneity is the PDI.[28] For calculating the average particle size and PDI, the most common method is Dynamic Light Scattering (DLS). When the PDI score is less than 0.3, it usually means that the formulation is homogeneous.
2. Zeta Potential
An essential measure of colloidal stability, zeta potential reveals information on the surface charge of nanoparticles. Electrostatic repulsion is stronger in particles with a high zeta potential (±30 mV or higher), which decreases aggregation and improves physical stability. Usually, electrophoretic light scattering is used for measurement.[29]
3. Morphology and Surface Structure
The surface features and shape of SLNs can be observed using SEM and transmission electron microscopy (TEM). To verify spherical form, surface smoothness, or the existence of surface imperfections, these techniques produce high-resolution pictures.
4. Efficiency of Drug Loading and Entrapment (EE%)
The term "drug loading" describes the total quantity of drug present in the SLNs, whereas "entrapment efficiency" describes the proportion of drug that was effectively captured. To ensure precise dosing, these characteristics are usually measured by ultracentrifugation followed by UV-Visible spectrophotometry or HPLC. [30]
5. Crystallinity and Polymorphic Behaviour
Drug absorption and release are influenced by the crystalline structure of the lipid matrix. Differential Scanning Calorimetry (DSC) and X-ray Diffraction (XRD) are used to study the melting behavior, degree of crystallinity, and polymorphic transitions of lipids. Reducing crystallinity or going through an amorphous transition can enhance drug entrapment.[31,32]
6. Thermal Analysis
Thermal behavior of lipid and formulation components can also be assessed using DSC. Information on the physical state, drug-lipid interactions, and compatibility can be gleaned from the existence of endothermic or exothermic transitions.
7. In Vitro Drug Release Studies[33]
The drug release profile from the SLNs under physiological settings can be better predicted with the help of these research Methods like the USP dissolving equipment, Franz diffusion cells, or dialysis bag methods are employed. In order to comprehend the release process, the collected data is frequently fitted to kinetic models, such as zero-order, first-order, and Higuchi.
8. Stability Studies
Stability testing involves subjecting the substance to several environmental factors such light, humidity, and temperature in order to measure how the drug content, particle size, and zeta potential change over time. The formulation's shelf life and optimal storage conditions can only be determined with the help of these research.[34]
Application of SLN:
SLN for parenteral
Researchers Wissing et al. (2004) examined the usage of parenteral SLN in great detail. With their lyophilization and/or sterilization provide excellent storage capacities and components that are physiologically well-tolerated, SLN are perfect for systemic delivery. Although they are too small to see with the naked eye, SLN can navigate the microvascular system after intravenous administration and, should they have a hydrophilic covering, prevent macrophage uptake. For this reason, SLN has been considered for gene transfer via viruses and non-viruses alike. It has been demonstrated that cationic SLN electrostatically binds genes directly, suggesting that it could be useful for cancer focused gene therapy. An additional application for the composition is to alter particle charges, which allows molecules with opposite charges to bind. Brain tumors, AIDS, neurological illnesses, and mental disorders are among the many central nervous system maladies that are frequently untreatable because certain powerful medications can block the blood-brain barrier . Coated hydrophilic colloids are more efficiently distributed throughout tissues and cross the blood-brain barrier. The preparation of stealth SLN with and without doxorubicin, Fundaro et al. (2000) discovered that the stealth nanoparticles were more prevalent in the blood 24 hours following intravenous therapy. [35, 36]
SLN for Respiratory
The lungs have a large surface area that medications can be absorbed through allowing them to bypass first-pass effects. The extremely thin alveolar walls of the deep lung cause medications to be aerosolized, with a size range of 1-3 μm, and hence absorbed rapidly. There is a strong relationship between lymphatic drainage and the pulmonary system's particulate-absorbing capacity. It is possible that SLN could be recommended as carriers for peptide or anticancer drugs used to treat lung cancer, thus increasing their bioavailability. After inhalation, the radiolabelled SLN was found to be significantly and noticeably taken up by the lymphatic system, according to an assessment of its biodistribution [37]. A recent study combined various solid lipid particle formulations with antitubercular drugs (rifampicin, isoniazid, and pyrazinamide) and their sizes ranged from 1.1 to 2.1 μm. It was subsequently decided to nebulize the formulations orally into the guinea pigs' lungs for direct delivery [38,39]. Pulmonary tuberculosis treatment is enhanced by nebulization of solid lipid particles containing antitubercular medications. This increases drug bioavailability and decreases dose frequency.
SLN for Ocular Application
Multiple instances of drug administration to the eyes by SLN have been documented [40]. The mucoadhesive and biocompatible properties of SLN make them ideal for targeting the eyes, since they increase pharmacological effects on the ocular mucosa and prolong its residence duration on the cornea. When it came to bramycin delivery vehicles, Cavalli et al. (2002) tested SLN in rabbit eyes. The aqueous humour bioavailability of the medicine was thereby substantially enhanced by SLN. Cavalli et al. (1995) also performed study on the administration of pilocarpine by SLN, a method commonly used to treat glaucoma. Their results in increasing the drug's ocular bioavailability were strikingly similar.
SLN for Cancer chemotherapy
In vivo and in vitro studies have evaluated the efficacy of several chemotherapeutic medications encapsulated in SLN during the last 20 years. A substance named tamoxifen has been included into SLN in order to prolong the drug's release following intravenous treatment for breast cancer. [41] Methotrexate and camptothecin-loaded SLN have been used to target tumors. With the goal of improving the drug's safety, bioefficacy, and efficacy in treating breast cancer and lymph node metastases, mitoxantrone SLN local injections were developed.
Oral SLN for antitubercular chemotherapy
Rifampicin, isoniazid, and pyrazinamide-loaded SLN systems for antitubercular medications have decreased dosage frequency and increased patient compliance. Sorbent diffusion was used in the production of the SLNs loaded with antitubercular medication.
SLN for potential agriculture
Combining SLN with essential oil of Artemisia arborescens L. reduced evaporation more than emulsions, making these systems an eco-friendly pesticide alternative in agriculture.[42]
SLN for Rectal
There are a handful of papers that discuss the use of SLN for rectal drug delivery. A rapid sedative effect was achieved by rectal administration of diazepam with SLN. We tested the bioavailability of SLN dispersions by administering them to rabbits. The lipid matrix does not help diazepam distribute rectally since it stays solid at room temperature. Lipids that break down at room temperature were the next target of their research.
SLN for Topical
Colloidal carrier systems like Solid lipid nanoparticle and Nanostructured lipid carriers are attractive for skin applications due to their characteristics and the many beneficial benefits they have on the skin. They are perfect for use on inflamed or injured skin because their lipid base is neither irritating nor harmful. The topical application of SLN has been the subject of extensive study. [43] Sun protection creams containing SLN are a relatively new application area.
CONCLUSION:
Solid lipid nanoparticles (SLNs) are one platform that has emerged as a result of nanotechnology's expansion of medication delivery possibilities. These have many benefits, including biocompatibility, controlled release, and enhanced drug stability. Extensive research has been conducted on several preparation strategies to improve their formulation efficiency. These approaches include solvent evaporation and high-pressure homogenization. We now have a better grasp of their physicochemical features due to developments in characterization technologies, which has helped us develop delivery systems that are both more stable and more effective. Problems such as polymorphic lipid transitions, limited drug loading capacity, and difficulties in producing on a big scale persist despite these improvements. Innovative lipid matrices, hybrid systems, and scalable production methods should be the focus of future research to overcome these limitations. Additionally, novel approaches to precision medicine, especially in the fields of neurology and cancer, may emerge from combining SLNs with targeted delivery and stimuli-responsive mechanisms.
REFERENCES
Avula Prameela Rani, G. Sandhya Vani*, A Review on Solid Lipid Nanoparticles: Preparation Techniques, Characterization, And Future Challenges, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 7, 3752-3763. https://doi.org/10.5281/zenodo.16526995
10.5281/zenodo.16526995
